Inflammation elicited by a subset of bacteria that inhabit the oral cavity such as Porphyromonas gingivalis (Pg) is a key facet of periodontal disease (PD). This chronic inflammation is thought to drive the destruction of both hard and soft tissues that in severe disease leads to tooth loss. Unexpectedly, elevated levels of the type 1 interferon, interferon (IFN)-1, as well as the interferon-induced protein Regulated upon Activation Normal T cell Expressed and Secreted (RANTES) has been detected in human PD tissues. This is unexpected as type 1 interferons are part of the innate immune response to viral infection. The role of these interferons in PD is essentially unknown. Interferon regulatory factors (IRF) are the principal transcriptional factors used for production of type 1 interferons. These transcription factors also regulate expression of other groups of genes known to be involved in inflammation. IRF3 and IRF7 signaling have been implicated in host response to periodontal pathogens;however, it is unclear precisely how interferon signaling participates in the establishment of a nidus of inflammation to periodontal pathogens. Our preliminary data identify increased expression of the ifnb1 gene from wild type macrophages cultured with Pg. Furthermore, culture of live Pg with macrophages from WT and IRF3-KO mice demonstrate a partial role for IRF3 in pro-inflammatory cytokine and chemokine production. Here we propose a detailed set of related studies to begin to characterize a poorly understood area of host response to periodontal pathogens, namely the role of IRF3 signaling and with establishment of inflammation elicited by Pg. These studies will pave the way for future expanded investigations to define the precise mechanisms underlying IRF3 signaling in the context of chronic inflammation and oral bone loss, markers associated with PD. The ultimate goal of this work is to begin to understand whether strategies to intercede in IRF3-signaling can be channeled to augment current PD treatment regimens. PUBLIC HEALTH RELEVANCE: Type 1 Interferons, such as interferon-1, are key mediators of the immune response to pathogenic virus infection. Emerging data indicate that type 1 interferons are produced as part of the host response to bacterial infections;however, this area is exceedingly understudied in the context of periodontal disease. Based on our preliminary data we propose a focused set of studies to 1- define production of and 2- mechanism underlying host type 1 interferon production to the periodontal pathogen Porphyromonas gingivalis.